Periodontitis is a chronic inflammatory response caused by bacterial plaque that has spread below the gum line. Starting in the early stages as gingivitis, the later stages of periodontitis involves inflammation of the gums, connective tissues, and bones surrounding the teeth i.e. alveolar bones. Prolonged inflammation causes degenerative loss of tissues supporting the teeth and alveolar bone loss, eventually leading to loss of teeth. Tooth loss, caused by the loss of alveolar bone, is one of the major problems in clinical dentistry. In fact, periodontitis is the primary cause of tooth loss. It is approximated that 140 million adults, in the United States alone, exhibit various stages of periodontal disease.
The periodontitis-associated inflammation occurring in the surrounding tissues that support the teeth is characterized by formation of infected “pockets” or spaces between the teeth and gums. These infected pockets contain debris, predominantly composed of microorganisms and their products (enzymes, endotoxins and other metabolic products), dental plaque, gingival fluid, food remnants, salivary mucin, desquamated epithelial cells, and leukocytes. Periodontal pockets are chronic inflammatory lesions, and as such are constantly undergoing repair. The condition of the soft tissue walls of the periodontal pocket results from a balance between destructive and constructive tissue changes. The destructive changes consist of the fluid and cellular inflammatory exudates and the associated degenerative changes stimulated by local bacterial infiltrate. The constructive changes consist of the formation of connective tissue cells, collagen fibers, and blood vessels in an effort to repair tissue damage caused by the inflammatory process. Healing does not go to completion because of the persistence of local irritants i.e., bacteria and the enzymes that they produce. These irritants stimulate fluid and cellular exudates, which in turn causes degeneration of the new tissue elements formed in the repair process. If purulent exudates are present in the infected pockets, it can contain living, degenerated and necrotic leukocytes (predominantly polymorphonuclear), living cells and dead bacterial cells, serum and a small amount of fibrin.
The most basic treatment for periodontitis is scaling and root planing procedures. These procedures involve manually removing calculus, plaque and other deposits, smoothing the root surface to rid it of necrotic tooth substances, and curetting the inner surface of the gingival wall of the periodontal pockets to separate away any diseased soft tissue. The procedures aim to eliminate the infected pockets by reattaching connective tissue and epithelium to the tooth surface. By eliminating the environment for the microorganisms to grow, scaling and root planing procedures can successfully obliterate the infected pockets. These procedures may result in the replacement of diseased soft tissue with new soft tissue from growth and differentiation of new cells and intercellular substances. However, scaling and root planing procedures are ineffective in stimulating the re-growth or replacement of destroyed bone and cementum caused by severe periodontitis. Hence, there is a need for reliable or predictable methods to regenerate, augment, or restore alveolar bone loss and cementum loss inflicted by periodontitis.
Another initial treatment for periodontitis is administration of antibiotics, which may be optionally performed in conjunction with scaling and root planing procedures. Tetracycline is the most commonly administered antibiotic for periodontitis; however, numerous other types of antibiotics can also be employed because human periodontal pockets harbor highly diverse populations of bacteria. In fact, a recent study by Paster et al. (Paster, B. J., Journal of Bacteriology, Vol. 183 (12), p. 3770-3790, 2001) recorded 91 different bacterial species or phylotypes from cultures collected from periodontal diseased sites in human patients. In those patients who suffered from refractory periodontitis, collected cultures revealed the presence of 213 different bacterial species or phylotypes present. Novel bacterial species or phylotypes, in addition to known putative periodontal pathogens such as Porphyromonas gingivalis, Bacteroides forsythus, and Treponema denticola, were observed in these cultures. In addition to tetracycline, other antibiotics, such as minocycline, as described in U.S. Pat. No. 4,701,320 (the entire disclosure of which is incorporated herein by reference), and amoxicillin and metronidazole, as described in U.S. Pat. No. 4,997,830 (the entire disclosure of which is incorporated herein by reference), have been employed for the treatment of periodontitis. Despite the effectiveness of antibiotics in reducing inflammation and bacterial infection, antibiotic administration, like scaling and root planing, is also deficient in stimulating re-growth or replacement of the destroyed bone and cementum caused by severe periodontitis.
A more dramatic therapy for patients who are not responsive to scaling and root planing procedures and/or antibiotic administration is periodontal surgery, such as gingivectomy or periodontal flap surgery. In gingivectomy, the dentist reshapes the unhealthy gum tissue in order to reduce the size of the infected pocket. Reduction of the pocket size allows the patient to hygienically maintain the pocket by routine brushing and flossing, thereby eliminating a favorable environment for bacterial growth. Periodontal flap surgery is performed also when scaling and root planing procedures are unsuccessful, especially when there is loss of bone or tissue detachment. In this procedure, incisions are made in the gums and the surrounding alveolar bone is re-contoured to assist in healing of the infected area. Since only one quadrant of the mouth can be operated on at a time, multiple visits to the dentist are required and the entire surgical procedure can extend over a period of a month or longer. In addition to the invasive nature and the inherent pain involved with surgery, both procedures of gingivectomy and periodontal flap surgery are insufficient in stimulating re-growth or replacement of the destroyed bone and cementum caused by severe periodontitis.
In an effort to address the problem of alveolar bone loss caused by periodontitis, therapeutic compositions containing substances that specifically stimulate osteogenesis in mammalian skeleton have been developed. One such substance is prostaglandin E1 (PGE1). In vitro studies, as described for example in Flanagan et al. (Flanagan, A. M. et al., Endocrinology, Vol. 130 (1), p. 443-448, 1992), have shown that culturing mammalian calvarial cells in the presence of PGE1 increases the formation of mineralized nodules. Formation of these nodules is advantageous because they give rise to osteoprogenitor cells, which are responsible for mediating the process of bone anabolism (Miller et al., Clinics in Plastic Surgery, Vol. 21 (3), p. 393-400, July 1994). The role of PGE1 in bone formation has been confirmed by in vivo studies performed on adult dog models. A study by Marks et al. (Marks, S. C. et al., J. Oral Pathol., Vol 17, p. 500-505, 1988) shows that local application of PGE1 can stimulate new bone formation adjacent to sites of delivery in the canine mandible long bone and that local delivery of PGE1 increases the thickness and appositional rate of alveolar bone in the canine mandible. A further study, also by Marks et al. (Marks, S. C. et al., J. Periodont. Res., Vol. 29, p. 103-108, 1994) shows that local delivery of PGE1 to the canine mandible increases alveolar bone height and regenerates cementum and periodontal ligaments around the premolars and molars of adult dogs. These in vivo studies demonstrate that PGE1 can promote osteogenesis and increase bone mass.
Recently, topical compositions comprising a synthetic and more stable PGE1 analog, called misoprostol, have been developed as conjunctive therapy with scaling and root planing procedures. As described, for example in U.S. Pat. Nos. 5,324,746 and 5,510,384 (the disclosures of which are incorporated herein by reference), these compositions are effective in treating periodontal disease and can also be used to treat damaged tissue caused by, for example, chemotherapy or radiotherapy. Other applications for compositions comprising misoprostol include regeneration of collagen-containing human tissue, such as skin, bone, connective tissue, and cartilage, as described for example in U.S. Pat. No. 5,994,399 (the disclosure of which is incorporated herein by reference).
An object of the present invention is to provide a pharmaceutical composition and methods that are more effective than misoprostol alone or current methods in regenerating bone and cementum in periodontal pockets of patients afflicted with periodontal disease.